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Pathology- Huntington's Disease
I. Definition & Epidemiology:
I. Definition & Epidemiology:
- Definition: HD is an inherited, neurodegenerative disorder resulting from a mutation in the HTT gene. This mutation leads to the production of a dysfunctional huntingtin protein.
- Epidemiology:
- Prevalence: 5-10 per 100,000 globally, with geographical variation.
- Onset: Typically 35-45 years, but can occur at any age.
- Sex: Affects men and women equally.
- Inheritance: Autosomal dominant (only one affected copy of the gene is needed to develop the disease).
- HTT Gene: Contains a CAG trinucleotide repeat sequence.
- Normal HTT: Less than 36 CAG repeats.
- Mutant HTT: More than 36 CAG repeats. The number of repeats directly correlates with disease severity and age of onset (more repeats = earlier onset, greater severity).
- Anticipation: The number of CAG repeats tends to increase in subsequent generations, leading to earlier onset and more severe disease in offspring. This phenomenon is known as anticipation.
- Huntingtin Protein (HTT): The protein encoded by the HTT gene has various cellular functions and is expressed throughout the body, but is most concentrated in the brain and testes.
- Mechanism of Disease: Mutated huntingtin protein is cytotoxic (toxic to cells), particularly affecting neurons in the caudate nucleus and putamen (basal ganglia structures crucial for movement control).
- Early Symptoms: Uncontrolled, jerky, involuntary movements (chorea).
- Progressive Disease: Over time, HD leads to progressive motor, neuropsychiatric (mood disorders, cognitive issues), and cognitive decline, ultimately culminating in dementia.
- Macroscopy: Significant atrophy (shrinking) of the caudate nucleus and putamen. Cortical atrophy may also be present.
- Histopathology: Marked neuronal loss in the caudate nucleus. Surviving neurons contain excessive amounts of the mutated huntingtin protein.
- Survival: Average survival is approximately 20 years from symptom onset, but varies depending on the number of CAG repeats (more repeats = shorter survival).
- Cause of Death: Often pneumonia or cardiac failure due to mutated huntingtin expression in cardiac muscle.
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